Targeting MET Exon 14 Skipping Mutations in NSCLC

The Relevance of MET Alterations to Targeted NSCLC Therapies

Martin Dietrich, MD, PhD, discusses the role MET alterations play as oncogenic drivers of non–small cell lung cancer.

Martin Dietrich, MD, PhD, assistant professor of Internal Medicine at the University of Central Florida, discusses the role MET alterations play as oncogenic drivers of non–small cell lung cancer (NSCLC).

MET amplifications and MET exon 14 skipping mutations are gene alterations found in the MET gene that are therapeutic targets for NSCLC. EGFR tyrosine kinase inhibitors (TKIs) target the cMET protein associated with the MET gene to reduce tumor growth, but these gene alterations are associated with EGFR resistance.

According to Dietrich, the MET exon 14 skipping mutation has demonstrated activity as an oncogenic driver for NSCLC and its presence is consistently correlated to responses with TKIs. Though MET amplifications are not as recognized as an oncogenic driver, they are also also a predictive biomarker for targeted therapies, and studies have shown that response rates of therapies are correlated to the level of amplification based on the number of copies of the MET gene.

Detection of MET alterations can guide therapeutic approaches but identifying MET alterations requires molecular biomarker testing through a next-generation sequencing (NGS) panel or fluorescence in situ hybridization (FISH) assay. Due to the difficulty of detecting MET exon 14 skipping mutations, RNA-based panels are used rather than DNA-based panels due to their greater reliability, Dietrich explains.

TRANSCRIPTION:

0:08 | There are 2 different kinds of alterations in the MET gene. In cMET, we find an overaccumulation of the receptor by splicing out the degradation domain in exon 14, accumulating MET at the surface. We also have overexpression by amplification. Those are 2 separate mechanisms of MET amplification; they both lead to activation of downstream targets. We are not certain what the level of MET amplification actually has to be before we can truly consider it an oncogenic driver. I think we see this in some of the response rates, that the level of MET amplification is highly correlating with the degree of response.

With [MET] exon 14, it is very different. There's a very clear-cut driver that correlates with very good responses unanimously across the board. We have much more to learn about the MET amplifications, but I think we're very certain—and this is reflected in the 2 approvals that we have—that MET exon 14 is a true oncogenic driver. Both share that they are not easy to detect biomarkers. You do need, preferably, an RNA-based panel for detection of the MET exon 14 skipping, [because] the splicing variants are not always reliably detected on DNA. For MET amplification, we either need a FISH assay or quantitative analysis by NGS. Those are the 2 differences that we that we need, so both fall into the category of what we're trying to do with NSCLC, which is comprehensive molecular testing on multiple platforms to ensure that we have all the biomarkers that are potentially actionable, or a marker for clinical trial [testing].